Normal organismal homeostasis is maintained through a careful balance of cell proliferation and cell death processes. Cancer cells, while rapidly undergoing division and expansion, may also undergo cell death. It is important to understand how cancer cells die or lose their susceptibility to the cell death process. We have shown that the susceptibility of cells at various stages of the neoplastic process to undergo apoptosis differs. In separate studies, we are pursuing the apoptotic pathway in response to oxidative damage. In studies following the role of p53 in this process, we have found that apoptosis also appears to require the p85 kinase. In addition we have found that the Rb protein may be a key player in the cellular decision whether to arrest or commit suicide following injury. In addition, we have also been examining the role of the EIA binding, p300 protein, as an integrator of multiple cellular responses. We have found that p300 can couple with the c-fos protein under conditions of cellular stress that result in apoptosis. The elevation of c-fos has been shown to be a key event in low serum induced apoptosis of hamster fibroblasts. We propose that the binding of c-fos to p300 is critical for the cellular decision to undergo cell death. In addition, we are beginning studies to examine the early gene response to a variety of agents that induce oxygen free radicals. We hope to use cDNA microarray technology to establish a molecular signature of the cellular response to this class of agents. Finally, we are examining the role of IGFI in protecting prostate cancer cells from apoptosis and the effect of dietary restriction in TRAMP transgenic mice in limiting prostate neoplasms. This is the final year for this project. Any further research will be done at NCI.